title: The natural killer cell response and tumor debulking are associated with prolonged survival in recurrent glioblastoma patients receiving dendritic cells loaded with autologous tumor lysates.
abstract: Recurrent glioblastomas (GBs) are highly aggressive tumors associated with a 6-8 mo survival rate. In this study, we evaluated the possible benefits of an immunotherapeutic strategy based on mature dendritic cells (DCs) loaded with autologous tumor-cell lysates in 15 patients affected by recurrent GB. The median progression-free survival (PFS) of this patient cohort was 4.4 mo, and the median overall survival (OS) was 8.0 mo. Patients with small tumors at the time of the first vaccination (< 20 cm3; n = 8) had significantly longer PFS and OS than the other patients (6.0 vs. 3.0 mo, p = 0.01; and 16.5 vs. 7.0 mo, p = 0.003, respectively). CD8+T cells, CD56+natural killer (NK) cells and other immune parameters, such as the levels of transforming growth factor β, vascular endothelial growth factor, interleukin-12 and interferon γ (IFNγ), were measured in the peripheral blood and serum of patients before and after immunization, which enabled us to obtain a vaccination/baseline ratio (V/B ratio). An increased V/B ratio for NK cells, but not CD8+T cells, was significantly associated with prolonged PFS and OS. Patients exhibiting NK-cell responses were characterized by high levels of circulating IFNγ and E4BP4, an NK-cell transcription factor. Furthermore, the NK cell V/B ratio was inversely correlated with the TGFβ2 and VEGF V/B ratios. These results suggest that tumor-loaded DCs may increase the survival rate of patients with recurrent GB after effective tumor debulking, and emphasize the role of the NK-cell response in this therapeutic setting.
authors.affiliation: Unit of Molecular Neuro-Oncology; Fondazione I.R.C.C.S. Istituto Neurologico C. Besta; Milan, Italy ; Department of Experimental Oncology; European Institute of Oncology - Campus IFOM-IEO; Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pellegatta
authors.forename: Marica
authors.initials: M
authors.lastname: Eoli
authors.forename: Simona
authors.initials: S
authors.lastname: Frigerio
authors.forename: Carlo
authors.initials: C
authors.lastname: Antozzi
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Bruzzone
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cantini
authors.forename: Sara
authors.initials: S
authors.lastname: Nava
authors.forename: Elena
authors.initials: E
authors.lastname: Anghileri
authors.forename: Lucia
authors.initials: L
authors.lastname: Cuppini
authors.forename: Valeria
authors.initials: V
authors.lastname: Cuccarini
authors.forename: Emilio
authors.initials: E
authors.lastname: Ciusani
authors.forename: Marta
authors.initials: M
authors.lastname: Dossena
authors.forename: Bianca
authors.initials: B
authors.lastname: Pollo
authors.forename: Renato
authors.initials: R
authors.lastname: Mantegazza
authors.forename: Eugenio A
authors.initials: EA
authors.lastname: Parati
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
keywords: IFNγ; NK cells; dendritic cells; glioblastoma; immunotherapy